Lung cancer is the leading cause of cancer death in the US, exhibiting a dismal five year survival rate of ~16%, underscoring the need for new therapeutic approaches. The recent development of targeted therapeutics that effectively treat lung cancer subtypes harboring specific driver mutations in EGFR, MET and EML4-ALK have made important inroads in treating these specific subsets of lung cancer. Despite these key advances, treatment options for mutant KRAS-driven lung adenocarcinoma (KRAS LADC), the most prevalent form of lung cancer, remain limited. We have identified protein kinase C? (PKC?) as an oncogene in KRAS LADC and lung squamous cell carcinoma (LSCC), the two major forms of non-small cell lung cancer (NSCLC). PKC? functions to maintain a tumor-initiating cell (TIC) phenotype in both of these NSCLC tumor types. Surprisingly however, our published and preliminary studies demonstrate that PKC? drives a TIC phenotype in KRAS LADC and LSCC through distinct signaling pathways. Preliminary data demonstrate that: 1) PKC? drives a KRAS LADC TIC phenotype by activating expression of the pluripotent stem factor NOTCH3; 2) PKC? activates NOTCH3 expression by recruiting the ELF3 transcription factor to the NOTCH3 promoter; 3) PKC? phosphorylates ELF3 at Ser68 to regulate ELF3 occupancy and activation of the NOTCH3 promoter; 4) a newly identified, highly potent and selective PKC? inhibitor inhibits LADC TIC cell behavior in vitro. Based on these data, we hypothesize that: 1) PKC? regulates ELF3 promoter occupancy on NOTCH3 and other gene targets involved in maintaining a LADC TIC phenotype; 2) the novel PKC?-ELF3-NOTCH3 signaling axis drives Kras-mediated LADC initiation and progression in mouse models of Kras LADC; 3) our novel, potent and highly selective PKC? inhibitor will exhibit anti-tumor activity in KRAS LADC, and PKC?-ELF3-NOTCH3 signaling intermediates will be useful predictive and pharmacodynamic biomarkers of response. These hypotheses will be tested in three interrelated specific aims to: 1) assess the role of PKC?-mediated ELF3 phosphorylation in NOTCH3 promoter occupancy, NOTCH3 expression and LADC TIC behavior; 2) assess the role of the PKC?- ELF3-NOTCH3 signaling axis in mutant Kras-mediated lung tumor initiation and progression; and 3) assess the potential of a novel highly potent and selective PKC? inhibitor as a therapeutic strategy for treatment of KRAS LADC. Successful completion of these aims will: 1) provide new mechanistic insight into the newly- identified PKC?-ELF3-NOTCH3 signaling axis; 2) assess the importance of this pathway in the maintenance of a LADC TIC phenotype; 3) identify novel targets for PKC?-ELF3-dependent transcriptional regulation; 4) assess the importance of the PKC?-ELF3-NOTCH3 signaling axis in LADC tumor initiation and maintenance; and 5) assess the utility of a newly-developed, highly potent PKC? inhibitor in the treatment of KRAS LADC. Given the poor clinical outcome of patients with KRAS LADC, and the dearth of therapeutic options, these studies may have widespread impact on the clinical management of these patients.